The loss of the female sex hormone--estrogen--in the climacteric can lead to phenomena which require therapy. Estrogens are steroid hormones which are derived from the tetracyclic C.sub.18 steroid estrane. Among the natural estrogens, one differentiates between estrone (E.sub.1), estradiol (E.sub.2) and estriol (E.sub.3), estrone and estriol being the physiologically most important. Hormone replacement with both these estrogens quickly leads to an improvement in psychological consciousness and in the long term to a favourable influence on the bone and lipoid metabolism. The last-mentioned factors represent effective prevention of diseases of the skeletal system and of illnesses of the heart circulation system. It has been proved without any doubt that E.sub.1 and E.sub.2 can prevent advancing osteoporosis in the climacteric and can slow the advance of arteriosclerotic vascular changes.
Against the said favourable effects there stands a risk, which is considered tolerable, from possible stimulating effects of the estrogens on the growth of hormone-dependent tumours of the genital tract (endometrium) and of the mammary gland. The known combination of estrogens with gestagens has the aim of minimizing the corresponding risks through the anti-proliferative action of gestagens in the uterus.
Examples of therapies with natural estrogens are:
1) The transdermal application of estradiol (for example Estraderm.RTM. TTS), PA1 2) the oral application of estradiol and its esters, PA1 3) the oral application of conjugated estrogens; these are obtained from the urine of gravid mares and are a mixture of different estrogens and PA1 4) the vaginal application of natural estrogens. The latter aims to remedy atrophy of the genital mucous membranes. PA1 Not effective for osteoporosis prophylaxis: PA1 Estriol, the medicament can however clear psychovegetative symptoms and local findings in the genital area.
As explained above, a disadvantage of therapy with such types of estrogens is their ability to cause uterine cancer (endometrium carcinoma) or breast cancer.
It has been proved that, by combining the aforementioned estrogens with a gestagen, the risk to those concerned of suffering an endometrium carcinoma is reduced to 1/6th of the risk to women treated only with estrogen. Examples of such combination therapies are described in DE-A-39 10 578, DE-A-39 08 130, DE 38 36 826 and EP 0 474 374.
However, a favourable effect on mortality from mastocarcinomas is not to be expected from a corresponding estrogen-gestagen combination. (L. A. Brinton "Menopause and . . . " New York, Academy of Sciences, 592, 357-362, (1990); R. A. Lobo, "Estrogen and Cardiovascular Disease" in "Multidisciplinary Perspectives on Menopause", published by M. Flint, F. Kronenberg and W. Utian, Annals of the N.Y. Acad. of Sciences, 592, pages 286-294 (1990)).
Breast cancer is the most frequent symptom of cancer in women over all. The theory is generally accepted that the mitogenic effect of the sum of the quantities of estrogen acting upon the mammary gland during life is a decisive (risk) factor for the occurrence of a cancerous disease of this organ (cf. B. E. Henderson, R. Ross and L. Bernstein "Estrogens as a cause of human cancer", The Richard and Hinda Rosenthal Foundation Award Lecture, Cancer Res., 48, 246-253, (1988); R. Clarke, R. B. Dickson and M. E. Lippman "The role of steroid hormones and growth factors in the control of normal and malignant breast" in "Nuclear Hormone Receptors", published by M. G. Parker, Academic Press, London, pages 297-319 (1991)).
The danger of the risk increase as regards illness from breast cancer is therefore a central factor in the assessment of the benefits and risks of hormone replacement therapy (HRT-Hormon Replacement Therapy; L. A. Brinton "Menopause and the risk of breast cancer", in Multidisciplinary Perspectives on Menopause. Ann, N.Y. Academy of Sciences, published by M. Flint, F. Kronenberg and W. Utian, 592, pages 357-362 (1990) review). In the case of longer-lasting therapy, various epidemiological studies suggested an increase in the relative risk by a factor of 1.5 to 3.1, the latter being in the cases where HRT had lasted more than 10 years (Table 3, page 359 of the aforementioned paper).
The situation is different in the case of estriol. On the one hand it is known that it can prevent or suppress the development of mastocarcinomas, but on the other hand it has hitherto been reported to have an inadequate therapeutic effectiveness within the scope of hormone replacement therapy (HRT). The latter has a particular importance for the prevention of osteoporosis. Thus, in an official statement by the Deutsche Gesellschaft fur Endokrinologie, the ineffectiveness of estriol for osteoporosis prophylaxis is expressly emphasized (cf. Deutsches Artzeblatt--Arztliche Mitteilungen, 85, 1322-1325, partic. 1325, 1-hand col.
Estriol is normally formed in the cycle and in pregnancy, whereby extraordinarily large quantities are expelled during pregnancy. From a pharmacological viewpoint, estriol is regarded as weakly-acting estrogen. The differences compared with E.sub.1 and E.sub.2 and with other synthetic estrogens are for example displayed by the fact that estriol does not significantly stimulate uterine weights when administered once to ovariectomized rats. Corresponding findings, which indicate little or no effect on the uterus, have also been made in studies involving women. Even comparatively high dosages of 5 mg E.sub.3 /day oral (H. W. Rudel and R. A. Kincl "Oral contraceptives. Human fertility studies and side effects" in "International Encyclopedia of Pharmacology and Therapeutics", Chapter 34, "Pharmacology of the Endocrine System and related drugs . . . ", edited by M. Tausk, Volume II, pages 385 et seq., Pergamon Press, London, (1972)) were not able to suppress ovulation in women, whilst this was clearly possible with estradiol and conjugated estrogens even at lower dosages.
However, in other test arrangements, in which estriol was applied in combination with "strong" estrogens, this substance proved to have an anti-estrogen action. Accordingly, estriol is itself estrogenous, but has an anti-estrogen action via the displacement of stronger estrogens from the receptor.
In particular, the proven anti-tumour effect of estriol in the induction and promotion phases of tumour development (H. M. Lemon, "Antimammary Cancerogenic Activity of 17.alpha.-ethinyl-estriol" Cancer 60, 2873-2881 (1987)) leads one to expect that no additional growth impetus at the tumour centre results from treatments which contain estriol in pharmacodynamically relevant formulation, but that, on the contrary, suitable therapy leads to a reduction in the mammatumour risk.
The properties of estriol, which are possibly not only unproblematical but even anti-carcinogenic compared with other estrogens, were discussed inter alia also by Foilingstad in "The Journal of the American Medical Association" 239, 29/30 (1978) and the clinical testing of this estrogen was recommended. Relevant comprehensive studies were carried out with 80 women in the postmenopausal stage over a period of 2 years by Lindsay et al. (R. Lindsay, D. M. Hart, A. MacLean, J. Garwood, A. C. Clark and A. Kraszewski (1979), Bone loss during oestriol therapy in postmenopausal women, Maturitas 1: 179), and the results were continuously evaluated throughout the test period, in particular as regards a possible anti-osteoporotic effectiveness of the substance with reference to bone mineral content. To the disappointment of the authors, it was shown that estriol developed no osteoprotective effectiveness in the bones of the treated women, even in dosage quantities of 12 mg/day oral. The ineffectiveness of estriol in the bones has now become standard knowledge in the relevant text books (cf. for example Freimut A. Leidenberger, "Klinische Endokrinologie fur Frauenarzte", Springer Verlag 1992, where, on page 356, it states word for word:
Reference is also made to the ineffectiveness of estriol for the indication discussed here in product information for preparations which contain estriol as active ingredient (cf. for example Jenapharm Arzneimittel: Sortima und Preise dated 01.07.1991, page 67).
Nor was this overall assessment influenced by the report produced by Blumin 1985 (cf. M. Blum, Clin. Exp. Obstet. Gynecol. 12, 1/2 (1985)) which describes a study involving 25 women in the postmenopausal phase. A vaginal cream containing 0.5 mg estriol/g was administered to the women before they went to sleep, daily for 2 weeks and then twice weekly in a quantity of 0.5 g in each case over a period of 4 months. An improvement was observed in some of the postmenopausal disorders, in particular the disorders connected with genitourinary atrophy and dyspareunia, whilst insomnia, sweating and hot flushes were not improved. Accordingly, it was necessary to additionally administer chlonidine to combat these symptoms. The author also investigated the ratio of calcium to creatinine and, from a slight reduction in this ratio during the investigative period, inferred an anti-osteoporotic action of the estriol. However, for a statement of this type, the investigative period was much too short, cf. Lindsay et al. op cit. and, moreover, this ratio alone is not meaningful since it depends inter alia on nutrition; investigations at the bone were not carried out or reported by Blum.
The fact that all cardia symptoms of the postmenopausal disorders in the study of estriol reported by Blum remained unaffected, with the result that chlonidine had to be additionally administered, suggests that the patients, as previously, suffered from estrogen deficiency.
On assessing the overall state of the art, it can therefore be established that estriol has hitherto been considered unsuitable by specialists for the treatment of climacteric osteoporosis.
It is the problem underlying the invention to provide means, with the help of which climacteric osteoporosis can be effectively combatted, without at the same time having to accept an increase in the risk of illness from breast cancer.
To solve the problem, it is proposed according to the invention to use estriol for the production of transdermal retard preparations which guarantee a continuous active ingredient release over at least 24 hours.